This COMRAD application continues a multisite collaboration, initiated under DA 012845, to conduct a prospective study to address critical issues in the genetic epidemiology of adolescent onset antisocial drug dependence. Addressing these issues requires sample sizes greater than a single site can reasonably attain, as well as the multidisciplinary expertise, of psychiatrists, psychologists, and behavioral and molecular geneticists, that is difficult to provide at a single site. Our rationale for focusing on persistent antisocial substance dependence that has its onset in adolescence is the guiding hypothesis that early onset, persistent, and pervasive behavior will reflect a biological vulnerability of the individual. We propose to conduct genetic and clinical descriptive studies of adolescent-onset antisocial drug dependence in the largest samples ever studied prospectively for this condition. With our Center sample (Center on Antisocial Drug Dependence, DA011015), this multisite collaboration will yield a total of approximately 800 probands with adolescent-onset substance and conduct problems, together with their siblings, re-assessed at five-year follow-up. We anticipate a final sample of ~600 persistent cases and ~200 non-persistent former cases, together with their siblings, and a sample of 600 community control subjects and their siblings (drawn from our existing community samples). To achieve this, we will complete the five-year follow-up of 1186 clinical probands and their siblings on whom we have Wave 1 assessments (Aim 1). We expect a 70 percent follow-up rate, which will yield a sample of 830 clinical probands aged 19 though 23 years at follow-up, and their siblings. Of these probands, 251 will be completed, at no cost to this application, as part of DA011015. The COMRAD will be funded to complete phenotypic assessements of the remaining 579 probands and their siblings and to carry out the following analyses of the entire sample. Aim 2: 1) Key predictors which were assessed during the adolescent assessment will be examined to determine whether they discriminate between proband cases that persist in their antisocial and substance use behaviors versus those cases that desist. 2) We will examine trajectories of adolescent substance use and antisocial behaviors and examine the role of contextual factors such as critical life transitions on the development of these behaviors. 3) We will explore possible new phenotypes by testing them for maximal heritability in the community samples and examining the patterns of familial transmission in the clinical samples. Aim 3: We will conduct genome wide, family-based, association analyses of persistent adolescent-onset antisocial drug dependence, using the ~600 persistent cases and their siblings, and ~600 controls and their siblings, and parental DNA when available. PUBLIC HEALTH RELEVANCE: Substance abuse/use disorder is a significant social and health problem. This multisite collaborative study of persistent adolescent-onset antisocial drug dependence provides a unique opportunity to assess differing developmental trajectories and clinical courses, the role of comorbidity, early onset, familial loading, and genetic influences on these behaviors.